Relevance to Autism

Tessadori et al., 2022 reported six individuals with de novo missense variants in the H4C3 gene presented with a neurodevelopmental syndrome characterized by intellectual disability and developmental delay; three of these individuals also presented with autism spectrum disorder (ASD). Additional functional assessment of the recurrent H4C3 p.Lys92Gln missense variant, which was observed in three patients (two of whom also presented with ASD) in this report, in zebrafish embryos demonstrated severe developmental defects in embryos expressing mutant H4C3 compared to wild-type protein. Tessadori et al., 2017 had previously reported three individuals with missense variants in H4C3 affecting the p.Lys92 residue who presented with a syndrome of growth delay, microcephaly and intellectual disability; expression of H3C4 mutants in zebrafish in this study recapitulated the developmental phenotypes observed in affected individuals.

Molecular Function

Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. Two molecules of each of the four core histones (H2A, H2B, H3, and H4) form an octamer, around which approximately 146 bp of DNA is wrapped in repeating units, called nucleosomes. The linker histone, H1, interacts with linker DNA between nucleosomes and functions in the compaction of chromatin into higher order structures. This gene is intronless and encodes a replication-dependent histone that is a member of the histone H4 family. Transcripts from this gene lack polyA tails but instead contain a palindromic termination element. This gene is found in the large histone gene cluster on chromosome 6.

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